Development of novel quinoline-NO donor hybrids inducing human breast cancer cells apoptosis via inhibition of topoisomerase I

Guiying Wu; Hui Zhong; Ying Wang; Li Chen; Jianbo Sun

doi:10.1016/j.bmc.2023.117530

Development of novel quinoline-NO donor hybrids inducing human breast cancer cells apoptosis via inhibition of topoisomerase I

Bioorg Med Chem. 2023 Dec 15:96:117530. doi: 10.1016/j.bmc.2023.117530. Epub 2023 Nov 10.

Authors

Guiying Wu¹, Hui Zhong¹, Ying Wang¹, Li Chen², Jianbo Sun³

Affiliations

¹ State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
² State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: chenli627@cpu.edu.cn.
³ State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: sunjianbo@cpu.edu.cn.

PMID: 37956506
DOI: 10.1016/j.bmc.2023.117530

Abstract

A number of NO-releasing quinoline derivatives have been designed and synthesized by introducing NO donor to quinoline carboxylic acid fragment. The anti-proliferation of all target compounds was evaluated against human cancer cell lines (HCT-116, MCF-7, and A549), MCF-7/ADR and normal cell (MCF-10A). Most compounds showed cytotoxic activity on cancer cells and drug-resistant cells with IC₅₀ values in the range of 0.62-5.51 μM. Importantly, these compounds showed low toxicity to normal cells (4.21-34.08 μM). Further mechanism studies showed that the most potent compound 9 could release high concentration of NO and inhibit the activity of topoisomerase I. In addition, 9 regulated apoptosis-related proteins, generated ROS and blocked MCF-7 cells in G2/M phase to induce cell apoptosis. Furthermore, the P-gp-mediated transport was also influenced by 9. And 9 could significantly inhibit the growth of tumor in vivo without observable organ-related toxicities. Overall, as a novel NO-releasing quinoline derivative, 9 was worthy for further in-depth study.

Keywords: Anticancer; Cytotoxic activity; NO-donor; Quinoline; Topoisomerase I.

MeSH terms

Antineoplastic Agents* / metabolism
Antineoplastic Agents* / pharmacology
Apoptosis
Breast Neoplasms* / drug therapy
Cell Line, Tumor
Cell Proliferation
DNA Topoisomerases, Type I / metabolism
Drug Screening Assays, Antitumor
Female
Humans
MCF-7 Cells
Quinolines* / pharmacology
Structure-Activity Relationship

Substances

DNA Topoisomerases, Type I
Antineoplastic Agents
Quinolines